The State of
Innovation in
Antibacterial
Therapeutics
by David Thomas, CFA and Chad Wessel
BIO INDUSTRY ANALYSIS
February 2022

About BIO
The Biotechnology Innovation Organization (BIO) is
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biotechnology companies, academic institutions, state
biotechnology centers and related organizations acrossthe United States and in more than 30 other nations.
BIO members are involved in the research anddevelopment of innovative healthcare, agricultural,industrial, and environmental biotechnology products.
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Access BIO Industry Analysis reports here:
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Introduction
Antibacterial drug discovery and development during the 20th century yielded one of the greatest
armaments available to physicians, with more than 90% of all antibacterial drugs discovered during thisperiod. Since the introduction of numerous antibiotic classes during the 1940s, deaths from bacterial
infections have been reduced significantly. However, this next century is already presenting challenges
that may render these older antibiotics obsolete. The COVID pandemic, which exposed multiple
preparedness shortcomings, has elevated attention to the increasing threat of drug-resistant strains ofbacteria. More than 1.2 million people worldwide are dying each year from antibiotic resistant infections
and it is estimated this number will grow to 10 million per year by 2050.1,2 In the U.S. alone, more than
2.8 million antibiotic-resistant infections occur each year, with more than 35,000 people dying as a result.3
The CDC, EMEA, WHO, IDSA, Pew, and other groups have issued warnings to public policymakers formore than a decade about the reduced effectiveness of last century’s antibiotic arsenal (see Appendix
A1 for the most recent pathogen threat list from CDC and WHO).
Millions of currently treatable infections could become life threatening as the prior innovative advantage
over bacteria wanes in the coming decades. Hospital acquired bacterial infections alone affect 1.7 million
patients per year in the U.S., with almost 100,000 dying as a result.4 A significant portion of these patientsacquire Clostridioides difficile, in large part due to taking 20th century antibiotics that harm beneficial
bacteria in the human gut.5 Skin infections affect 14 million patients in the U.S. each year and are
responsible for more than 3 million visits to emergency departments.6 The American Lung Association
reports that Streptococcus pneumoniae infects the lungs of 900,000 Americans each year, with otherbacteria responsible for even more pneumonia cases.7 There is also a rising threat from bacterial sexuallytransmitted diseases. According to a 2019 report by the U.S. CDC, Gonorrhea and Syphilis are at theirhighest case levels since 1991, and Chlamydia has reached 1.7 million cases.8 Prior to Covid, the leading
cause of death from infectious disease globally was Mycobacterium tuberculosis infection (TB), with 1.6
million deaths resulting from more than 10 million cases per year.
This report investigates recent investment into antibacterial innovation and the current clinical pipelinethat will help bridge the gaps in the antibacterial armamentarium. In our previously published research,drug development investment for many common chronic diseases was found to be declining and low
relative to total healthcare burden on society. In that survey of under-funded disease areas, antibiotic
investment was also found to be low and not trending upward with the rest of the industry. Unfortunately,over the same time period the total number of infections has risen along with more reports of antibiotic
resistance. The lack of investor interest can be seen by contrasting venture investment into antibiotics
vs. cancer over the last decade (Figure 9). Oncology companies raised close to $7 billion in 2020 (up
900% from 2011), whereas antibiotic companies raised just $0.16 billion (less than what they raised 10
years prior). This prompted the ongoing investigation to expand our analysis beyond privately funded
companies. Specifically, we investigate funding industry-wide and determine to what extent thisweakness in funding has impacted innovative antibacterial drug candidates.
		Murray, C. et al. (2022). Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet, accessed online
January 20, 2022 at https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02724-0/fulltext
2
		Report to the Secretary-General of the United Nations. (2019). NO TIME TO WAIT: SECURING THE FUTURE FROM DRUG-RESISTANT
INFECTIONS. United Nations interagency Coordination Group on Antimicrobial Resistance. Accessed October 2021 from https://www.who.int/publications/i/item/no-time-to-wait-securing-the-future-from-drug-resistant-infections (see Appendix A1 for a list of
specific strains and threat levels.)3
		CDC AR Threats Report (2019), accessed October 2021 from: https://www.cdc.gov/drugresistance/biggest-threats.html
4		Hague, M., et al. (2018). Health care-associated infections – an overview. Infect Drug Resist, 11, 2321–2333
5
		Center for Disease Control and Prevention (2015). Nearly half a million Americans suffer from C. difficile infections in single year.
Retrieved from https://www.cdc.gov/hai/dpks/deadly-diarrhea/dpk-deadly-diarrhea.html
6		Hersh, A., et al. (2008). National Trends in Ambulatory Visits and Antibiotic Prescribing for Skin and Soft-Tissue Infections. Arch InternMed, 168(14), 1585-159. and company press release (https://melinta.com/melinta-therapeutics-announces-commercialavailability-of-kimyrsa/)
7
American Lung Association. Accessed October 2021 Retrieved from: https://www.lung.org/lung-health-diseases/lung-disease-lookup/pneumonia/what-causes-pneumonia. Other bacteria include Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila,
8			Center for Disease Control and Prevention (2019). New CDC Report: STDs Continue to Rise in the U.S. Retrieved from: https://www.
cdc.gov/nchhstp/newsroom/2019/2018-STD-surveillance-report-press-release.html
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We begin the report with an historical perspective on what antibacterial innovation over the past century
has yielded. Categorizing all FDA approved antibacterials according to strategic approach and moleculartarget allowed us to assess the current pipeline for novel targets. To investigate funding gaps beyond
venture investment, we also analyzed the last 10 years of clinical trial starts – an industry-wide proxy forinvestment and overall interest, that includes large and small public biopharma companies. In addition,
we assess public market investment into antibacterial-focused emerging biotech companies.

Key Takeaways for the State of Antibacterial Therapeutic Innovation• Approved Antibacterial Drugs: Although there have been 164 FDA-approved direct-acting
antibacterial new chemical entities (NCEs) since the early 1900s (Figure 1), only one newmolecular target NCE has been approved over the last 35 years, illustrating a need to broaden
the antibacterial discovery engine (Figure 2). There have been 11 indirect-acting NCEs
approved, including seven drugs that work to extend the activity of existing drugs and fourmonoclonal antibodies specific for exotoxins.
• Pipeline: The breadth and novelty of the antibacterial clinical-stage pipeline is insufficient tomeet the ongoing threat of wide-spread infection from drug-resistant strains. The clinicalpipeline contains 54 direct-acting novel chemical or biochemical entities and 10 microbial
entities (Figure 3). However, of the non-microbial candidates, 61% have targets for whichmarketed drugs already exist. More than 38% of candidate programs are indicated for C.
difficile and TB, leaving only 44 drugs for other pathogenic bacteria. Only 10 of these 44
candidates have a novel target. There have been 14 indirect-acting NCEs in the clinical pipeline,
including nine that work to extend the activity of existing drugs and five monoclonal
antibodies specific for exotoxins.
• Emerging Company Contribution to Innovation: Small companies discovered 81% of theantibacterial therapeutics being tested in the clinic. Large biopharmaceutical companies
discovered 12%, and small non-profit organizations discovered 7%, of the antibacterial
therapeutics being tested in the clinic (Figure 4).
• Clinical Trial Success Rates: The calculated success rate from Phase I to FDA approval during
the period 2011-2020 was 16.3% for an antibacterial new chemical entity (NCE). This is morethan twice the overall industry success rate of 7.9%. For novel targeting NCEs, the success rate
was 13%, with only three novel target drug programs transitioning at Phase III during thisten-year period (Figure 8).
• Emerging Company Investment: Venture capital funding of U.S. antibacterial-focusedbiopharma over the last decade was $1.6 billion compared to oncology’s $26.5 billion (Figure 9).
IPOs for 12 U.S. antibacterial-focused biopharma brought in just $0.7 billion over this period,
compared to 109 U.S. oncology companies raising $12 billion (Figure 10). This equates to almost
17x less funding of antibacterial vs. oncology companies during this time.
• Clinical Trial Initiations: Clinical trial initiations for antibacterial NCEs declined 33% whencomparing the five-year period 2016-2020 vs. 2011-2015 (from 55 down to 27 starts, Figure 11).
• Potential solutions to strengthen the antibacterial pipeline: 1) Early-stage investment (pushmechanisms for research), 2) regulatory incentives, 3) late-stage investment (push mechanisms
for development), 4) market-based mechanisms (pull incentives), and 5) reimbursement reform.

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Definitions
Antibacterials defined herein are direct-acting therapeutics that stop bacterial growth (bacteriostatic)or kill bacteria (bactericidal) or indirect-acting therapeutics that either enhance the effectiveness of
direct-acting drugs or inhibit exotoxins secreted by bacteria. This definition for antibacterial therapeutics
includes small molecules, proteins, nucleic acids, bacteriophage, and live bacteria. The microbial consortia
and single strain bacterial medicines (“microbiome therapeutics”) that can prevent target organism
growth are included.
We have included mycobacteria in the definition of bacteria for this report. Of the more than 60 species
that fall under the Mycobacterium genus, M. tuberculosis drug resistant strains are considered one of
the biggest threats in the world today. (The reason Mycobacteria are excluded in some antibacterial
pipeline reports is the highly differentiated molecular structures outside the inner cell membranecompared to gram-negative and gram-positive bacteria. Although all three types of bacteria have a
peptidoglycan layer beyond the inner membrane, mycobacteria have a thick layer of lipophilic mycolic
acids.9 These structural differences are important in drug design and optimal drug penetration but canlimit the breadth of infections that the drug can be used for).
The term NCE (New Chemical Entity) is used throughout this report and includes biologics, polymers
and synthetic peptides in addition to small chemical entities. Live bacteria products are included in the
broader group of “new antibacterial therapeutics.” Although we did not include reformulated NCEs,
there are previously approved compounds with newly identified secondary targets and mechanisms ofaction. These compounds provide important clinical benefits through incremental innovation. For example,
rifabutin has been reformulated and developed for carbapenem resistant Acinetobacter baumannii(CRAB) as it was discovered to access its primary target in a new species through a unique mechanism.

9

		Brown, L., et. al. (2015). Through the wall: extracellular vesicles in Gram-positive bacteria, mycobacteria and fungi. Nature Reviews
Microbiology, 13, 620–630

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FDA Approved Antibacterial Therapies
For this report, we investigated every drug marketed in the U.S. since the first antibacterial drug (Salvasaran)
debuted in the early 1910s.10 Since that time, there have been 164 FDA approved direct-acting novel
chemical entities. Multiple resources were used to compile this list of FDA approved NCEs: theEvaluatePharma database, the NIH NCATS Insight Drugs database, FDA websites, medical textbooks,
and prior reviews on the topic.11 There are 28 direct-acting NCEs approved outside the U.S. that are
excluded from this analysis. It should be noted that all but one of these ex-US antibiotics work by thesame strategic approaches as those approved in the U.S.12 There have been 11 FDA approved indirectacting antibacterial agents approved. These approved drugs work either as combinations to extend thehalf-life of existing antibiotics (e.g., lactamase inhibitors), or as antibodies against exotoxins.
There are nine established antibiotic strategies for fighting bacterial infections through direct-acting
antibacterials (Figure 1). The first two use the disruption of either the bacterial cell membrane or thesynthesis of their outer cell wall. Both are key features for maintaining unicellular structural integrity andare core approaches that comprise 43% of the approved antibacterial NCEs. Three of the nine approaches
target the central dogma of cellular life (the ability of a cell to use DNA to make RNA, and RNA to makeproteins). Of these three, the approach with the most approved NCEs is protein synthesis (27%), of which
the ribosome itself is most targeted. Three other strategies target enzymes of important metabolic
pathways (fatty acids, folic acid, and energy production). Lastly, there are prodrugs that, once insidebacteria cells, are converted to reactive species (such as free radicals) and damage multiple targets (suchas DNA, ribosomes, membranes, and various enzymes). This group has been assigned to the “macromoleculardamage” strategy.
As can be seen in Figure 3, only one novel target has had an NCE approval in the last three decades.
The ATP synthase inhibitor bedaquiline was FDA approved in 2012 for TB infections. Prior to this there
had not been a single novel target NCE approval since 1987, when the isoleucyl-tRNA synthetase inhibitor,and natural product, mupirocin, was approved. For non-TB drugs, that implies 36 years of no NCE
approvals for a new target based on this antibacterial definition.13 Peak discovery and development ofnovel targets occurred between the 1940s and 1960s period, when 15 new targets received NCE approvals.
This compares to only three new targets for the subsequent three decades.
Innovation has not been limited to new targets, however. There have been significant contributions in
the form of NCEs for validated targets (i.e., FDA approval) that offer extended strength against resistantstrains, better patient experience (e.g., ease of use, limited side effects, oral delivery, and better efficacy).
Looking through that lens at the last 30 years we found 53 NCE approvals for established targets (Figure 3).
Below, we describe how previously approved drugs work on the specific target families that were
outlined in Figure 1. Following this introduction to established antimicrobial strategies, we review thecurrent clinical pipeline’s new antibacterial strategies. All pipeline therapeutics reviewed herein for PhaseI through NDA/BLA filing are new, with no prior indication approval. However, as some pipeline therapeutics
continue to work through similar target and mechanism as last century’s drugs, we further separate thepipeline by novelty status of targets.

		Zaffiri, L., et. al. (2012). History of antibiotics. From salvarsan to cephalosporins. J Invest Surg, 25(2), 67-77.
EvaluatePharma: https://www.evaluate.com, NCATS: https://drugs.ncats.io/, Peterson, J. (1996). Medical Microbiology. 4th edition, andWaller, D., Sampson, T. (2014). Medical Pharmacology and Therapeutics, Fourth Edition. Publisher: Saunders
12		One exception is fusidic acid, isolated from Fusidium coccineum in the 1960s and unique among the translation inhibitors in that it
binds to GTP-hydrolyzing elongation factor G (EF-G). U.S. development of the drug was suspended.
13
		There have a been four approvals for antibody against exotoxins (Anthrax, and C. diff), but these stop severity and do not stop
growth or kill bacteria. Gene knockouts for most exotoxins have been shown to not inhibit bacterial growth.
10
11

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HOW FDA APPROVED ANTIBACTERIALS WORK

9 Strategies for Direct-Acting Antibacterials
21 Targets (106 Active/164 Approved NCEs)
penicillin-binding proteins (31/68)
Ala racemase and ligase (2/3)
D-Ala-D-Ala termini (4/4)
arabinosyl transferase (1/1)
C55-isoprenyl pyrophosphate (1/1)
UDP-NAG enolpyruvyl transferase (1/1)

1. Cell Wall
2. Membrane

membrane permeability (6/6)

3. Fatty Acid Synthesis
4. Folic acid Synthesis
5. Energy Metabolism
6. Biomolecular Damage

enoyl ACP reductase (2/2) [mb]ATP synthase (1/1) [mb]aspartate decarboxylase (1/1) [mb]dihydropteroate synthetase (7/15)
dihydrofolate reductase (1/1) [mb]Targets of nitro reactive species (RS) (3/4)
Targets of riminophenazine RS (0/1) [mb]Targets of cyclic arsenic RS (0/2)

Proteinribosome, 30S (17/21)
ribosome, 50S (12/14)
ribosome, 70S intersubunit bridge (1/2)
isoleucyl t-RNA synthetase (1/1)

7. Protein
Synthesis
RNA

Indirect-acting antibacterial NCEs:
4 Exotoxin mAbs (i.e. Anthrax, C. diff)
7 Beta-lactamase inhibitors

8. RNA
SynthesisDNA[mb] = mycobacterium specific target

RNA polymerase (6/6)

9. DNA
Synthesis

topoisomerase (9/18)

Figure 1. Diagram of currently employed drug targeting strategies to kill or prevent bacteria growth. Of the 164 NCEs
approved, 106 remain actively marketed. Shown in parenthesis after the target name is the number of active NCEs,
followed by the total number of NCEs approved.

TIMELINE OF FDA APPROVED DIRECT-ACTING ANTIBACTERIAL NCES 1900-2019
decadeNCEs

New Target

before 1940

7

2

1940-1949

11

6

1950-1959

22

4

1960-1969

22

4

1970-197922

2

1980-1989

27

2

1990-1999

24

0

2000-200911

0

2010-2019

18

1

164

21

Antibacterial NCE approvals
Antibacterial NCE approvals for new target
27
22

22

22

24
18

11

11

2

20102019

20002009

1
19901999

2

19801989

419701979

419601969

6
19401949

before1940

219501959

7• I changed this from
into 1 chart.
• I tried to center thetarget approval #s,bars are small.
• colors can change,
the new target barout.

Figure 2. Timeline of 164 NCE FDA approvals for antibacterials by decade approved. The 21 new target approvals are also
shown by decade first NCE was approved.

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5Strategy #1. Drugs that Target Cell Wall Synthesis
The antibacterial approach with the most FDA drug approvals is inhibition of the bacterial cell wall.
Multiple classes of enzymes and ancillary molecules are required for cell wall synthesis and maintenance.
As they are not found in human cells, these proteins and prokaryotic-specific molecules make for good
drug targets. Another advantage these targets have for therapeutic intervention is their location outside
the cytoplasmic membrane.14 The following are six cell wall target families that have FDA approved drugs:
penicillin binding protein (PBP), alanine racemase, arabinosyl transferase, C55-isoprenyl pyrophosphate,
D-Ala-D-Ala terminus of NAG-NAM-peptide, and UDP-NAG enolpyruvyl transferase. The disadvantageof these approved treatments, which is a common theme for the majority of antibacterials reviewed
below, is that multiple modes of resistance have developed due to widespread use over the last 80 years.
Penicillin binding protein (PBP) antibacterials: Of the 21 targets and target families listed in Figure 1,
the penicillin binding protein (PBP) target family has received the most NCE approvals, with a total of
68 NCEs approved by the FDA since their introduction in the 1940s. Less than half of these remain on
the market today. The 31 actively sold in the U.S. are classic beta-lactam structures that fall into four mainchemical classes: penicillins, cephalosporins, carbapenems, and monobactams. These antibacterials
have been used against a broad range of aerobic and anaerobic gram-positive and gram-negative organisms.
However, resistance to beta-lactam antibacterials has evolved based on two premises: beta-lactamase
production and mutational evasion of the PBP genes. Lactamases cleave the beta-lactam ring inactivating
the antibacterial drug. In other resistant bacteria, mutations evolve lower affinity PBPs to the beta-lactam
drugs making them less specific and less inhibitory.15 As bacteria have multiple PBPs (E. coli has morethan 10, for example), they can compensate for therapeutic stress applied to one subtype.16
Not shown in Figures 2 and 3, are the beta-lactamase inhibitors. On their own they do not haveantibacterial activity, thus do not meet the definition of direct-acting antibacterials in this report but
have immense value in increasing the longevity of decades old beta-lactam drugs facing resistance.
Seven innovative beta-lactamase inhibitors have been approved for use in combination with beta-lactam
drugs for resistant bacteria.
Alanine racemase/ligase antibacterials: One of the early building blocks of the cell wall synthesis
process is D-alanine, the stereoisomer of the more common amino acid, L-alanine. D-alanine is converted
from L-alanine by alanine racemase. Two of the D-alanine amino acids are then linked via peptide bondby alanine ligase before being used in the pentapeptide-sugar-lipid components of cell wall synthesis.
Two alanine racemase/ligase inhibitors were approved in the 1950s and 1960s, and one, Cycloserine,
remains in use today. Cycloserine is a structural analog of D-alanine that fits into the active site of both
enzyme targets needed for peptidoglycan synthesis. Cycloserine is indicated for the treatment oftuberculosis (TB) and urinary tract infections (UTIs). Resistance to cycloserine has developed throughmutations in multiple genes.17

		Liu, Y., et al. (2016). The Membrane Steps of Bacterial Cell Wall Synthesis as Antibiotic Targets. Antibiotics 5(3), 28
		Zapun, A. et al. (2008) Penicillin-binding proteins and b-lactam resistance. FEMS, 32, p.361-385
16
		Sauvage, E. et al. (2008). The penicillin-binding proteins: structure and role in peptidoglycan Biosynthesis. FEMS, 32, p.234-258
17Chen, J. et al. (2017). Identification of novel mutations associated with cycloserine resistance in Mycobacterium tuberculosis.
Antimicrob Chemother.
14
15

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D-Ala-D-Ala terminus antibacterials: There are four drugs approved that target the D-alanine-D-alanine(D-Ala-D-Ala) terminus of the cell wall NAG-NAM-peptide chain, thus preventing transpeptidase
elongation and cross-linking of the peptidoglycan cell wall. The most well-known drug within this target
family is vancomycin, a cyclic glycopeptide approved in 1958 for gram-positive infections. Unfortunately,
vancomycin resistant strains have developed through gene transfer of five genes involved in circumventing
the requirement for D-Ala (for some strains, this means replacement by D-Lac).18 Vancomycin-resistantenterococci (VRE) and Vancomycin-resistant S. aureus (VRSA) are represented in the CDC and WHO toppriority pathogen lists (Appendix A1). Three other glycopeptide drugs with a similar mechanism havebeen approved in the last 15 years.
Arabinosyl transferase antibacterials: The drug ethambutol is the only approved drug that inhibits
arabinosyl transferase. It is specific to mycobacteria as it inhibits polymerization of arabinogalactan, asaccharide polymer attached to mycolic acids in mycobacteria.19 Ethambutol has been used for thetreatment of pulmonary tuberculosis (TB). Over production of the transferase gene can lead to resistance.20
C55-isoprenyl pyrophosphate antibacterials: In 1948 bacitracin was approved for use as an injectableantibiotic to treat staphylococcus infections.21 Its mechanism of action involves binding to C55-isoprenyl
pyrophosphate. No other drugs in this class have been approved. Resistance can develop through geneacquisition of efflux and transporter pumps.22
UDP-NAG enolpyruvyl transferase antibacterials: In the 1970s, fosfomycin was approved for thetreatment of bladder infections. Fosfomycin inhibits UDP-NAG enolpyruvyl transferase (sometimes
referred to by its gene name, MurA), which is part of the initial steps in the cytoplasm required for thebuilding blocks of cell wall synthesis (specifically, UDP-N-acetylmuramyl-pentapeptide).23 Resistancecan develop through mutations that inactivate the nonessential glycerophosphate transporter renderingbacteria resistant to fosfomycin.24

Cong, Y., et al. (2020). Vancomycin resistant Staphylococcus aureus infections. J Adv Res. p.169–176
		Alderwick, L. et al. (2015). The Mycobacterial Cell Wall – Peptidoglycan and Arabinogalactan. Cold Spring Harb Perspect Med.
20
Belanger, A.E. et al. (1996). The embAB genes of Mycobacterium avium encode an arabinosyl transferase involved in cell wall arabinan
biosynthesis that is the target for the antimycobacterial drug ethambutol. Proc Natl Acad Sci.
21
The original approval for bacitracin was for a systemic injectable in 1948. In 2020 the U.S. FDA sent a request to manufacturers to withdraw
this injectable form from the market. Bacitracin remains commonly used as a topical treatment for dermal infections.
22
Ma, J., et al. (2019). Bacitracin resistance and enhanced virulence of Streptococcus suis via a novel efflux pump. BMC Vet Res. P.15: 377
23
Liu, Y., Breukink, E. (2016). The Membrane Steps of Bacterial Cell Wall Synthesis as Antibiotic Targets. Antibiotics 2016, 5(3), 28.
Retrieved from: https://www.mdpi.com/2079-6382/5/3/28/htm
24Castañeda-García A, Blázquez J, Rodríguez-Rojas A (2013). Molecular Mechanisms and Clinical Impact of Acquired and Intrinsic Fosfo�
mycin Resistance. Antibiotics, 2(2). 217–36.
18
19

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Strategy #2. Drugs that Disrupt the Cell Membrane
The cell membrane is not as rigid as the cell wall and can become porous, making it a good target forgram-negative species of bacteria, which are reliant on a two-membrane architecture and less dependent
on a thick cell wall. Examples of chemical classes that function in this manner are linear amphipathic
peptides, polymyxin cyclic peptides, lipopeptides, and amphipathic small molecules.25 The first approved
peptide antibacterial (1942) was the linear amphipathic peptide Gramicidin, which is so disruptive tomembranes it was only used as a topical formulation to prevent skin infections. The same restrictions
apply to the antiseptic chlorhexidine, a cationic polyguanide compound, as its membrane disruption is
not selective for microbes and can disrupt fragile blood cells.26 Three marketed polymyxins were approvedin the 1950s-1960s: Polymyxin B, Polymyxin E, and a prodrug of Polymyxin E.27 They are used for bacterial
conjunctivitis and skin infections and are specific to gram negative bacteria. The single lipopeptide
approved is the natural Streptomyces compound daptomycin (FDA approved in 2003 and marketed as
Cubicin). Another approved treatment under this strategy is Daptomycin which aggregates withphosphatidylglycerol components of the cell membrane causing pores or holes. This causes ion gradientdependent systems, such as respiration, to cease operating functionally.28 Daptomycin is differentiatedfrom others in this group in that, in addition to skin infections, it can be used for blood infection causedby gram-positive S. aureus.29

Strategy #3. Drugs that inhibit fatty acid synthesis
Bacteria rely heavily on multi-enzyme complexes for the synthesis of fatty acid substrates that will befurther processed as components on the cell membrane, cell wall, and for mycobacteria, the mycolicacid lipid layer. Fatty acid synthesis in bacteria involves at least seven enzymes that are distinct fromthose used by mammalian cells and thus make for great antibacterial targets. One of these enzymes
has been successfully drugged: enoyl-ACP reductase. The trans-2-enoyl-ACP reductase has multiple
isoforms that that can handle longer chain fatty acids in different organisms including: FabI (E.coli andother gram-negative), FabK (Streptococcus pneumoniae), and InhA (Mycoplasma).30 InhA, which canbind longer chain acyl groups, is the target of isoniazid and its derivative, ethionamide (both marketedsince the 1950s and 1960s, respectively). The widely marketed compound Triclosan inhibits FabI in
numerous non-mycobacterial strains. However, resistance to these drugs can be gained through single
point mutations in the reductase enzyme’s active site.31,32

Strategy #4. Drugs that inhibit folic acid synthesis
Although some categorize the folate pathway as part of nucleic acid synthesis, there are other metabolic
functions (e.g. amino acid synthesis) where folate (tetrahydrofolate, THF) plays a role. Thus, we haveseparated folic acid synthesis into its own strategy. There are two enzymes in the THF pathway targetedby approved drugs, dihydropteroate synthetase and dihydrofolate reductase. As humans get folate
from diet, these enzymes are unique to bacteria making them great antibiotic targets. The first enzyme,
dihydropteroate synthetase, ligates a phosphorylated pteridine and para-aminobenzoate (PABA) to
Waller, D., Sampson, T. (2014). Medical Pharmacology and Therapeutics, Fourth Edition. Publisher: Saunders
Liu, J. et al. (2018). Cytotoxicity evaluation of chlorhexidine gluconate on human fibroblasts, myoblasts, and osteoblasts. J Bone Jt
Infect, 3(4): 165–172. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098817/
27
Bergen PJ, Li J, Rayner CR, Nation RL (2006). Colistin methane sulfonate is an inactive prodrug of colistin against Pseudomonas
aeruginosa. Antimicrobial Agents and Chemotherapy 50 (6): 1953–8.
28
Pogliano, J., et al. (2012). Daptomycin-Mediated Reorganization of Membrane Architecture Causes Mislocalization of Essential Cell
Division Proteins. Journal of Bacteriology, 194, 17 (2012). To an extent, all the above membrane disrupting drugs could impact energy
production through cellular respiration, but as there are multiple functionalities being hit, we have placed within membrane
disruption more broadly.
29
FDA prescribing information for Cubicin. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/
label/2017/021572s059lbl.pdf
30
Rana, P., et al. (2020). FabI (enoyl acyl carrier protein reductase) - A potential broad spectrum therapeutic target and its inhibitors.
European Journal of Medicinal Chemistry, 208. Retrieved from: https://www.sciencedirect.com/science/article/abs/pii/
S0223523420307297
31
		Dessen, A. et al. (1995). Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis. Science, 267(5204):163841. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/7886450/
32
Bernardes-Génisson, V. et al. (2013). Isoniazid: an update on the multiple mechanisms for a singular action. Curr Med Chem, 20(35),p4370-85. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/23931278/
25
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make dihydropteroate (DHP), which is then converted to DHF (by DHF synthase). DHF is then combinedwith glutamate by dihydrofolate reductase to form THF. There have been 15 FDA NCE approvals for thedihydropteroate synthetase enzyme (the first being in the 1930s) and only two for dihydrofolate reductase(approved in the 1940s and 1960s). Dihydropteroate synthetase inhibitors are dominated by the sulfonamide
and sulfone chemical class antibacterials that work by mimicking the PABA substrate in the reaction.
4-Aminosalicylic acid and trimethroprim are the two drugs that inhibit dihydrofolate reductase.

Strategy #5. Drugs that inhibit energy metabolism and respiration
Although there are two drugs in this category, both used to treat TB, they are quite different. The first
represents the only new target for an antibacterial in more than 30 years: ATP synthase. Bedaquiline
was approved by the FDA in 2012 and marked the first TB drug approved in 40 years.33 The second drugin this group is Pyrazinamide, approved in 1971. By tagging aspartate decarboxylase for degradation,
mycobacterium cannot make the beta-alanine needed to generate pantothenate, the main componentof coenzyme A (CoA). CoA is a critical enzyme cofactor for metabolic pathways.34 Aspartate decarboxylase
is a differentiated target from humans as human do not make their own pantothenic acid (theessential vitamin B5).

Strategy #6. Drugs that cause broad damage to macromolecules
There are a few antibacterial NCEs marketed in the U.S. that do not fit into the single target paradigm
as described above. They exert pleiotropic cellular dysfunction, in large part due to the derivatives andbyproducts (i.e. reactive oxygen species) generated once the drug is inside the bacterial cell. For example,
nitrofurans and nitroimidazoles have a nitro group that can be reduced by nitroreductases to activate
reactive secondary compounds and free radicals.35 These reactive species then target multiple sites in
the cell, causing direct damage to DNA, ribosomes, various proteins, membranes and energy respiration
systems exhibiting potent antimycobacterial activity.36,37 Nitrofurantoin and Metronidazole, approved in
the 1950s and 1960s, respectively, are two of the three active drugs representing the nitro reactive species
in Figure 1. For both of these drugs, prior studies have shown DNA modification as well as destructionof energy metabolism.

33
34
35

36

37

Mahajan, R. Bedaquiline. (2013). First FDA-approved tuberculosis drug in 40 years. Int J Appl Basic Med Res, 3(1), 1-2
Gopal, P et al. (2020). Pyrazinamide triggers degradation of its target aspartate decarboxylase. Nature Communications, 11, 1661
Moreno, S. et al. (1984). Distinct reduction of nitrofurans and metronidazole to free radical metabolites by Tritrichomonas foetushydrogenosomal and cytosolic enzymes. Journal of Biological Chemistry, 259, p.8252–8259
Zuma, H. (2019). An update on derivatisation and repurposing of clinical nitrofuran drugs. European Journal of Pharmaceutical
Sciences, 140, 105092. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/31634556/
Le VVH, Rakonjac J (2021) Nitrofurans: Revival of an “old” drug class in the fight against antibiotic resistance. PLoS Pathog, 17(7):e1009663. Retrieved from: https://doi.org/10.1371/journal.ppat.1009663

BIO Industry Analysis

9The third marketed drug generating nitro reactive species is the nitroimidazole Pretonamid, approvedin 2019 under the Limited Population Drug Pathway (LPAD pathway) for TB. It was previously believed
to be specific to mycolic acid synthesis pathway, but more evidence suggests a broader targeting of
the activated species explaining its ability to work on rapidly growing and latent mycobacterial cells.38,39,40
The structurally similar compound Delamanid (OPC-67683) is approved outside the U.S. but currently at
Phase III in the U.S. (See Appendix A4 for more detail on the categorization of these compounds.)
Clofazimine, approved in the U.S. for leprosy (Mycobacterium leprae infection) in the 1980s, does nothave a nitro group but is believed to be reduced by bacterial oxidoreductases and oxidized by oxygento form unstable intermediates that damage cell membranes and guanine bases of DNA (particularly
mycobacteria and gram-positive bacteria).41,42,43 Although Clofazimine has been withdrawn from the U.S.
market (as indicated in Figure 1), it can still be obtained through the National Hansen’s Disease(Leprosy) Program.
The third target group using this strategy of damaging a wide array of biomolecules contains two drugs
no longer on the market: Arsphenamine (Salvarsan) and neoarsphenamine (NeoSalvarsan). These were
the first chemical agents used specifically to kill bacteria, primarily Treponema pallidum (for Syphilis).
Their use began in the early 1910s, but both were discontinued due to toxicity and the introduction of
penicillin in the 1940s, respectively. The arsphenamines contain a cyclic arsenic structure responsible for
their antibacterial properties. It is possible that that they bind thiol groups of enzymes involved in energy
metabolism and other important cellular functions.44 Other arsenic compounds used to fight parasitic
infections use a similar strategy. For example, the arsenic containing antiparasitic Melarsoprol irreversibly
binds to thiol groups on pyruvate kinase, a key enzyme in energy metabolism.45

Strategy #7. Drugs that Inhibit Protein Synthesis
There are numerous differences in prokaryotic vs. eukaryotic cell translation that allow for specific targetingof drugs to block protein production. There are also multiple proteins and RNA macromolecules tochoose from along the four-step process of translation: aminoacyl-tRNA assembly, initiation, elongation,and termination. The second largest group of FDA approved NCEs (after inhibitors of penicillin binding
proteins) target the bacterial ribosome at either the 30S or 50S subunit (21 and 16 NCE approvals,
respectively), most working at the early initiation stage of translation . One other ribosomal binding drug
is differentiated from the others as it targets the bridge between the 30S and 50S subunits. The outlier
in the group acts at the early tRNA synthesis stage. Drug that targets these translational components
of bacteria are described below.

Thakare, R., Dasgupta, A., Chopra, S. (2020). Pretomanid for the treatment of pulmonary tuberculosis. Drugs Today, 56(10):655-668.
Baptista, R., Fazakerley, D.M., Beckmann, M. et al. (2018). Untargeted metabolomics reveals a new mode of action of pretomanid (PA824). Sci Rep, 8, 5084.
40
FDA Press Release, (2019). FDA approves new drug for treatment-resistant forms of tuberculosis that affects the lungs. Accessed Nov
2021: https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-resistant-formstuberculosis-affects-lungs
41		Gopal, M. et al. (2013). Systematic review of clofazimine for the treatment of drug-resistant tuberculosis. INT J TUBERC LUNG DIS,
17(8) 1001–1007.
42
Yano, T., et al. (2011). Reduction of Clofazimine by Mycobacterial Type 2 NADH: Quinone Oxidoreductase. J Biol Chem,
286(12): 10276–10287.
43
Cholo, M. et al. (2012). Clofazimine: current status and future prospects. Journal of Antimicrobial Chemotherapy. 67(2), 290–298
44Shen, S., et al. (2013). Arsenic Binding to Proteins. Chem Rev. 113(10), 7769–7792 and Yarnell, A. (2005). Salvasaran. C&EN, 83, 25
45
Sharma, S., et al. (2017). Approaches to Design and Synthesis of Antiparasitic Drugs. Pharmacochemistry Library, 25, 1-577
38
39

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BIO Industry Analysis

Half of the 30S ribosome targeting NCEs are tetracycline derivatives and the other half are aminoglycosideentities. Both chemical classes were introduced starting in the late 1940s. The tetracyclines inhibit bindingof aminoacyl-tRNA to the ribosome. They are used to treat gram-positive and gram-negative infections.
Resistance has developed through efflux transport (pumping antibacterials back out of the cell) andthrough mutations of the ribosome. The aminoglycosides work in a similar manner at the 30S ribosome
aminoacyl-tRNA site but may also have a membrane disrupting mechanism. They are more active against
gram-negative than gram-positive infections and do not work as well against anaerobic bacteria.
Resistance to aminoglycoside drugs has developed through bacterial enzymatic modification of
the drug itself.
50S ribosome inhibitors include the macrolides (e.g., azithromycin), amphenicols (e.g., chloramphenicol),oxazolidinones (e.g., linezolid), pleuromutilins (e.g., retapamulin), streptogramins, (e.g., quinupristin/
dalfopristin combo therapy), and lincosamides (e.g., lincomycin). The first four chemical classes arrived
on the market in the U.S. during the 1940s and 1950s, while the lincosamides were approved in the 1960s.
Since the adoption of these antibacterials in the middle of the 20th century, various forms of resistancehave developed. Like the aminoglycosides, the macrolides, streptogramins, and amphenicols can be
modified to an inactive form or they can be exported through efflux mechanisms. Lincosamide andoxazolidinone resistance stems from ribosomal mutation.
Two structurally similar NCEs, the cyclic peptides viomycin and capreomycin bind between the twolarge subunits of the bacterial ribosome. The binding location suggests that these drug works by locking
the tRNA in a pre-translocation state.46 Although viomycin was approved in 1953 for TB, it was discontinued
in the U.S. after the 1971 introduction of capreomycin.
The non-ribosomal binding target in this group is isoleucyl t-RNA synthetase. Mupirocin binds thistarget and depletes the cell of functioning Ile-tRNA. It was approved by the FDA in 1987 as a topicalcream for Staphylococcus aureus (G+) or Streptococcus pyogenes (G+).

Strategy #8. Drugs that Inhibit RNA Synthesis
Rifamycins inhibit RNA synthesis directly through RNA polymerase. Six rifamycin class NCEs wereapproved between 1971-2018 to make up this target family and all six remain on the market (Figure 1).
Rifamycins are active in gram-positive bacteria, gram-negative bacteria, and mycobacteria in part due
to how selective they are compared to human RNA polymerase. Clinical use range is broad and includes
diseases caused by M. tuberculosis, M. avium, Brucella spp. (G-), (Brucellosis/Mediterranean fever)Legionella pneumophila (G-), (Legionnaires’ disease), S. aureus, N. meningitis, H. pylori, and traveler’s
diarrhea caused by gram-negative bacteria. 47 Chronic use has been shown to generate resistant bacteria
through specific changes in the RNA polymerase beta subunit gene.48

46

47
48

Zhang, L., et al. (2020.) The structural basis for inhibition of ribosomal translocation by viomycin. Proceedings of the National Academyof Sciences, 117 (19) 10271-10277.
Waller, D., Sampson, T. (2014). Medical Pharmacology and Therapeutics, Fourth Edition. Publisher: Saunders
Goldstein, B. (2014). Resistance to rifampicin: a review. J Antibiot (Tokyo). 67(9):625-30.

BIO Industry Analysis

11Strategy #9. Drugs that Inhibit DNA Synthesis
The quinolones and fluoroquinolones make up the majority of marketed NCEs that target DNA
synthesis machinery. They work by binding to topoisomerase enzymes, primarily DNA gyrase (atopoisomerase II enzyme) and topoisomerase IV, that unwind DNA during replication, introduce
negative supercoils, and remove knots found in the circular chromosome. The first generation ofquinolones initiated through nalidixic acid’s approval in 1964 but it has since been discontinued.
Subsequent generations of quinolones were approved throughout the 1980s (e.g., ciprofloxacin, 1987),
1990s (e.g., levofloxacin, 1996), 2000s (e.g., Gemifloxacin, 2003), and even as recently as 2017(delafloxacin). Of the 17 FDA approved quinolone NCEs, eight remain on the market today. As withother NCEs described above, resistance can come from either mutations of the topoisomerase or
through efflux pumps.
Only one non-quinolone drug in this target family has been approved: the aminocoumarin DNA
Gyrase B inhibitor, novobiocin, isolated from Streptomyces. However, this drug was withdrawn fromthe U.S. market in the 1980s after more than 30 years on the market.49
For indirect-acting antibacterials, there are five targets. Beta-lactamase is a target for six FDA approved NCEs that work only in combination of existing PBM-targeting lactam drugs. A seventh drug
also extends the activity of lactam drugs, but targets a human kidney enzyme, dihydropeptidase. The
remaining three targets are exotoxins: Bacillus anthracis protective antigen (two approved mAbs), C.
difficile Toxin B (one approved mAb), and Clostridium botulinum nerve toxin serotypes A-G (one approved polyclonal antibody mix for serotypes A, B, C, D, E, F, G). These secreted factors from bacteriacause damage to the immune system and can be fatal, making anti-toxin therapeutics a high priority.
One advantage they have over the antibacterials described above is that they place little selective
pressure on the pathogen itself and thus are less likely to result in drug resistance strains.

49

Lowe, D. (2021). Novobiocin Returns? But Not as an Antibiotic. Science.

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BIO Industry Analysis

Clinical Pipeline for Antibacterials
The total clinical pipeline for new antibacterial therapeutics consists of 64 unique new antibacterial
therapeutics, with 31 (48%) having novel targets. The number of drug programs (drug-indication pathways)
for these 64 therapies is 72. Only eight drugs have a secondary indication pathway program and noneof the therapeutic entities have more than two.
The antibacterial therapeutics pipeline is broken out by phase for total indication pathways and forindividual entities in Figure 3. As is the case with most disease area pipelines, the largest number ofprograms reside in Phase II. For antibacterial indication programs, there are 31 programs in Phase II vs.
25 programs for Phase I and 15 programs for Phase III.
For the 64 new antibacterial therapeutic entities illustrated by Phase in Figure 3, we counted the mostadvanced phase for each unique drug candidate. There are more new antibacterial therapeutic entities
in Phase II (16) vs. those for established targets (13). In Phase I and III, there are slightly fewer drugcandidates with novel targets vs. those with targets previously approved. In Phase I, there are 10 novel
target programs vs. 13 established target programs. In Phase III, there are 5 novel target programs vs. 6
established target programs. Only one drug candidate with an approved target was at the FDA NDA
filing stage as of October 2021.50
CLINICAL-STAGE DRUG PIPELINE FOR DIRECT-ACTING ANTIBACTERIALS BY PHASE
64 NCEs
72 Drug Indica�on Programs

Novel Target# NCEs (most advanced phase)

35
30
25

18

31

13

14
12
10

15

15

Approved Target

16

16

25

20

13

10

8

10

5

6

5
0

# NCEs (most advanced phase)20

1Phase 1

Phase 2Phase 3

NDA/BLA

6

4
2

0

0

Phase 1

Phase 2Phase 3

1

NDA/BLA

33 NCEs with Approved Target
31 NCEs with Novel Target

Figure 3. The clinical pipeline for direct-acting antibacterials by Phase (as of October 2021), based on Biomedtracker’sclassification methodology by Phase of development as well as company website information. Five programs listed as“Ex-U.S.” in the Biomedtracker database are included here by Phase based on independent research of company
websites. (The “Ex-U.S.” listing in Biomedtracker database implies the companies have not yet intended toseek FDA approval.)50

For a comparison of our pipeline to recent reports from the WHO and the PEW Charitable Trust, see Appendix A4.

BIO Industry Analysis

13Clinical Pipeline by Originating Company
More than 60 companies and non-profit research institutes are developing the 64 clinical-stage drugcandidates to meet the growing need for differentiated antibacterials. As shown in Figure 4, the numberof new antibiotic therapies originating from small companies accounted for 80% of the drug discoveries,
8% originated from non-profit institutes and universities, and 12% originated from large companies.

CLINICAL-STAGE DRUG PIPELINE FOR ANTIBACTERIALS BY ORIGINATING ENTITY

51

Approved Target
Novel Target

8

5
Small
Companies

Non-Profits

Large
Companies

Figure 4. Antibacterial clinical pipeline NCEs by discovering entity. Non-Profits includes independent R&D institutes,
and universities. Small companies are defined as less than $1 billion in revenue.

14

BIO Industry Analysis

Clinical Pipeline by Modality and Delivery
The direct-acting antibacterial therapeutic clinical pipeline modalities and modes of delivery can befound in Figure 5. There are 47 small molecule NCEs (73%) and 17 biologics (27%) in the clinical pipeline.
Traditional systemic small molecule “antibiotics” account for 97% (45 of 47) and topical small molecules
account for 3% (2 of 47) of the small molecule pipeline NCEs. Of the 17 biologics, there are 7 systemic
biologics (injectables for proteins or bacteriophage) and 10 live bacterial products that are orally delivered
to the gut. Figure 5 also separates the modality and delivery characteristics of the pipeline. There arethree times as many small molecules for approved targets than for novel targets, whereas all 17 biologics
are for novel targets.
CLINICAL-STAGE DRUG PIPELINE FOR ANTIBACTERIALS BY MODALITY AND DELIVERY SYSTEM
Modality/Delivery for NCEs

NCE type

Pipeline by Modality

Pipeline by Delivery

Total

%

NCE type

Target

Total%

NCE type

Target

Total%

Systemic small molecules

45

70%

Small Molecule

Approved

33

52%

Systemic

Approved

31

48%

Topical small molecules

2

3%

Biologic (bacterial)

Approved

0

0%

GI

Approved

00%

Protein injectibles

58%

Biologic (protein)Approved

00%TopicalApproved2

3%

Phage injectibles

2

3%

Biologic (phage)

Approved

00%Systemic

Novel

21

33%

Live oral/gut
biotherapeutics

10

16%

Small Molecule

Novel

14

22%

GI

Novel

10

16%

Total

64

100%

Biologic (bacterial)

Novel

10

16%

TopicalNovel

Biologic (protein)

Novel

5

8%

Total

Biologic (phage)

Novel

Total

2

3%

64

100%

0

0%

64

100%

Figure 5. Antibacterial clinical pipeline NCEs by modality and delivery. * GI, gastrointestinal for microbiome therapies.
Systemic includes inhaled therapies (n=2).

BIO Industry Analysis

15

Clinical Pipeline by Strategy and Target
Figure 6 shows the direct-acting antibacterial clinical pipeline by therapeutic strategy and target family.
There are currently 13 different strategic approaches being used across the 64 therapeutics in the clinicalpipeline. Within these 13 strategies, 28 targets are being pursued. With live bacterial products grouped
as a single target family (gut microbiome), there are 18 total novel targets and 10 targets with priorapproval history. Each of these target families, and the drug candidates targeting them, are described below.
ANTIBACTERIAL CLINICAL PIPELINE STRATEGIES & TARGETS

Antibacterial Clinical Pipeline Strategies & Targets
13 Strategies
28 Targets

Protein A (surface antigen) (1)Endotoxin (surface antigen) (1)Not disclosed (surface antigen) (1)FimH (cell adhesion) (1)
T3SS (secretion system) (1)membrane permeability (8)enoyl ACP reductase (2)Targets of nitro reactive species (RS) (1)Targets of riminophenazine RS (1)12. Microbiome

1. Cell Surface Targets*
2. Cell Wall
3. Membrane
4. Fatty Acid Synthesis
5. Energy Metabolism
6. Biomolecular Damage
7. Cytoskeleton
ProteinFlora, Live biotherapeutics (10)13. A. baumanni targetRNA

Not disclosed (target of A. baumanni) (1)

10. DNA
topoisomerase (4)DNA pol IIIc (1)18 Novel Targets in green
10 Approved Targets in red(# of new antibacterials)

penicillin-binding proteins (7)DrpE1 (3)
Lysis by lysins (2)Lysis by phage (1)ATP synthase (2) [mb]cytochrome bcc (1) [mb]Not disclosed (cholesterol) (1) [mb]FTsZ (cytoskeletal protein) (1)8. Protein
Synthesis

ribosome, 30S (1)ribosome, 50S (5) [2mb]leucyl t-RNA synthetase (1) [mb]met t-RNA synthetase (1)9. RNA
Synthesis

RNA polymerase (2) [dual-acting NCEs]

11. DNA
Synthesis

DNA (groove binding) (2)DNA (editing) (1)*includes adhesion/Internalization and surface mAb targets

Figure 6. The clinical pipeline for 64 new antibacterial therapeutics by strategy and target. The 31 new antibacterial
therapeutics with novel targets are shown in green and the 33 new antibacterial therapeutics with approved targets areshown in red. Flora refers to microbiome approaches to re-establish healthy bacteria or introduce bacteria that can killdisease-causing bacteria. See text for more information on the three undisclosed targets.

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BIO Industry Analysis

Drug Candidates with Novel Targets in the Clinical Pipeline (31 therapeutic candidates
for 18 novel targets)
1.

Cell wall synthesis: DrpE1 (3). There are three drugs in the clinic that target decaprenylphosphoryl-beta-D-ribofuranose oxidoreductase (DrpE1). This enzyme holds a key role insynthesizing glycolipid precursor units of mycobacterium cell walls.51 All three drugs targeting
DRpE1 are in Phase II and indicated for M. tuberculosis.

2.

Cell wall lysis by lysins (2). There are two biotherapeutics in the clinic that utilize enzymatic
lysis to kill bacteria. One is a purified phage lysin for S. aureus (in Phase III) and the other apurified lysin specific for C. difficile (in Phase I).

3.

Cell wall lysis by bacteriophage (1). One phage therapy has started human testing for drug
resistant Pseudomonas aeruginosa.52 This approach utilizes the bacteriophage life cycle
process of progeny release that releases lysins to break the outer wall and membraneof the bacteria.

4.

Cell division: Cytoskeleton (1). The bacterial protein product of the FtsZ gene is akin to tubulin
in eukaryotic cells, with a similar role in cell division. There is one Phase I drug targeting FtsZ in
the pipeline and it has the QIDP designation.

5.

Surface target: Secretion Systems (1). Type III Secretion System (T3SS) of pathogenic gramnegative bacteria is a multiprotein molecular syringe that can inject adhesion andinternalization factors into human cells.53 Certain T3SS inhibitors have demonstrated a
reduction in growth and are thus included in this analysis of antibacterials (as separate fromanti-virulence factors that would only lesson the toxicity of the secreted factor). Russia’s
Ftortiazinon is being studied for use in Complicated Urinary Tract Infections (cUTI) caused by
P. aeruginosa.54

6.

Surface target: Endotoxin (1). Endotoxin is a lipopolysaccharide residing on the outer cellsurface of gram-negative bacteria. Within the structure of endotoxin is the O-polysaccharide
moiety that has been targeted by mAbs. One of the mAbs is in Phase II for P.
aeruginosa infection.

7.

Surface target: Protein A (1). Protein A is a unique cell surface protein in that interacts withconstant regions of human antibodies. While this has been known for more than 40 years andexploited for mAb purification, protein A is now the target itself for S. aureus infection. One
antibody specific to S. aureus protein a is in Phase I/II.

8.

Surface target: Unknown for mAb (1). One unknown surface protein target (and likely multiple
targets) is the antigen of a pooled polyclonal cocktail from survivors of C. difficile infection. This
product is currently in Phase II.

		 Degiacomi, G. (2020). Promiscuous Targets for Antitubercular Drug Discovery. Appl. Sci., 10(2), 623.
DrpE1 uses FAD to oxidize decaprenylphosphoribose into decaprenylphosphoarabinose, the arabinose donor subunits used forpolymers lipoarabinomannan and arabinogalactan.
52
Adaptive Phage Therapeutics press release. (2021). Adaptive Phage Therapeutics Highlights the Publication of a Case Study ofInvestigational Phage Therapy for an Antibiotic-Resistant Bacterial Infection in a Child. Retrieved from: https://www.aphage.com/
adaptive-phage-therapeutics-highlights-the-publication-of-a-case-study-of-investigational-phage-therapy-for-an-antibioticresistant-bacterial-infection-in-a-child/
53
Hotinger, J., Pendergrass, H., May, A. (2021). Molecular Targets and Strategies for Inhibition of the Bacterial Type III Secretion System(T3SS); Inhibitors Directly Binding to T3SS Components. Biomolecules, 11(2), 316.
54
NIH/U.S. National Library of Medicine. (2021). Safety and Efficacy Study of Ftortiazinon in the Treatment of Patients with ComplicatedUrinary Tract Infections Caused by P. Aeruginosa.
51

BIO Industry Analysis

17

9.

Surface target: FimH (1). Bacteria have protein-based filament rods that allow them to attach
to host cells. Of the many subunits that comprise these rods protruding from the bacteria cellsurface, is FimH (a fimbria-mannose attachment protein. A fimbira is a long appendage
protruding from the bacteria). FimH has been shown to bind N-linked glycans on urinaryepithelial cells.55 The antibody in Phase I is being tested to treat and prevent UTIs without
inducing antibiotic resistance.

10. Energy metabolism: cytochrome cc (1). As described above, the ATP synthase inhibitor
Bedaquiline (SIRTURO™) was approved in 2012 for pulmonary multi-drug resistant tuberculosis.
This small molecule drug represents the first novel target approval in more than 30 years, as
shown in Figure 2. Another target within the respiratory chain upstream of ATP synthase iscytochrome cc, an enzyme akin to the cytochrome bc1 complex (complex III) found in humanmitochondria and respiring bacteria.56,57 There is one NCE in the clinical pipeline targeting
mycobacterium cytochrome cc.
11. Metabolism: Cholesterol catabolism (1). A small molecule drug targeting cholesterol
catabolism is in Phase I. Certain bacteria, such as M. tuberculosis, can survive on cholesterol
and this candidate would effectively prevent this optional lipid energy source.
12. Translation: Leucyl-tRNA synthetase (1). There is one drug candidate for leucyl-tRNA
synthetase in Phase II for M. tuberculosis. There is currently one other FDA approved tRNA
synthetase inhibitor, Mupirocin, but it is specific for isoleucyl-tRNA synthetase.
13. Translation: Methionine tRNA synthetase (1). The second tRNA synthetase in the pipeline is
the methionine-tRNA synthetase in Phase II to treat C. difficile.
14. DNA synthesis: DNA polymerase (1). The prokaryotic replisome involves at least 10 enzymes
working in a coordinated fashion to synthesize DNA. One of these enzymes, topoisomerase,
was discussed above under the DNA synthesis strategy. DNA polymerase III, the primary
enzyme in the DNA synthesis process, would be a new target for this category. Currently, there
is one DNA polymerase IIIc inhibitor in Phase II for C. difficile.
15. DNA damage: Cas-3 editing (1). One therapy in the pipeline utilizes engineered bacteriophagewith CRISPR-Cas3 to target E. coli for destruction. The therapy has completed Phase 1b for
urinary tract infections.
16. DNA: direct binding (2). There are two DNA minor groove binding NCEs being developed totreat C. difficile infections, with one in Phase III and the other in Phase II.
17. Gut and reproductive tract flora (10). Although not a specific molecular target, this group oflive biotherapeutics target microbiome and bile acid restoration shown to exert growthpressure on C. difficile.58,59 Nine of the ten live biotherapeutic treatments are indicated for C.
difficile, with one indicated for bacterial vaginosis. The majority of these gut microbiome
therapies are microbial consortium, with two containing lactobacillus, two containing nontoxic strains of C. difficile, and others containing more complex mixtures of bacterial species orproprietary clonal variants. A number of programs are progressing successfully with three now
in Phase III, four in Phase II, and three in Phase I.

55
56
57

58

59

Sauer, M., et al. (2016). Catch-bond mechanism of the bacterial adhesin FimH. Nature Communications, 7, Article number: 10738.
Sone, N., et al. (2001). A novel hydrophobic diheme c-type cytochrome. Biochim Biophys Acta, 1503(3), 279-90.
Lu, P., et al. (2018). The anti-mycobacterial activity of the cytochrome bcc inhibitor Q203 can be enhanced by small-molecule
inhibition of cytochrome bd. Nature Scientific Reports, 8, Article number: 2625.
Mullish, B., Allegretti, J. (2021). The contribution of bile acid metabolism to the pathogenesis of Clostridioides difficile infection.
Therapeutic Advances in Gastroenterology, 14.
Taur, Y., Pamer, E. (2014). Fixing the microbiota to treat Clostridium difficile infections. Nat Med, 20(3), 246-247.

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BIO Industry Analysis

18. Unknown target for Acinetobacter baumannii (1). The third NCE for an unknown target is amacrocyclic peptide that is specific for A. baumannii (G-), the highest priority pathogen threat
according to both CDC and WHO. This gram-negative bacterium is associated with hospitalacquired infections that target the urinary tract, lungs (pneumonia), blood, or in wounds.60,61
Carbapenem-resistant Acinetobacter caused an estimated 8,500 infections in hospitalized
patients in the United States in 2019.62

Drug Candidates with Approved Targets in the Clinical Pipeline
1.

Penicillin-binding proteins (7 NCEs). As described above, the penicillin binding protein (PBP)
target family has a long history in drug development, with 68 FDA approved NCEs since the1940s. Development of non-lactam containing drugs was once the hope for innovative
targeting for a new repertoire of PBP inhibitors, but this has not panned out as seen in theseven NCEs in the current clinical pipeline.63 Six of the seven NCEs are modifications of betalactam structures of the past. Some have advanced properties, such as cell entry advantages orless susceptibility to beta lactamase degradation. The unique NCE in this group is not a classic
beta lactam drug and in fact has dual activity, inhibiting not only PBPs but also lactamases. Of
the seven NCEs targeting PBPs, three have approvals outside the U.S. The most advanced
drug in the pipeline, and only NDA-stage drug found in our analysis, is a beta lactam drug
approved ex-U.S.

2.

Cell membrane permeability (9 NCEs). The polymyxins and peptide mechanisms for pore
formation in bacterial membranes were described above and both serve as a starting point for
NCEs that work using this strategy, albeit with unique properties and perhaps slightly different
mechanisms. Three new polymyxins are in early stages of clinical testing for generalindications. Three synthetic amphipathic peptides are in the clinic, two in Phase I and one in
Phase II. Two small chemicals are also in this category of membrane disruptors, with one in
Phase IIb for Staphylococcal infection and one in Phase IIb for joint infections.

3.

FA synthesis: Enoyl ACP reductase (1): There are two NCEs in the clinical pipeline that target
the staphylococcal FabI enzyme. One is in two Phase II trials, one for skin infections (QIDP) and
one for joint infections. The other NCE is in Phase I for skin infections with specificity for drug
resistant S. aureus (G+).

4.

Energy Metabolism: ATP Synthase (2). Nearly 10 years after the landmark approval in 2012 of
the first ATP synthase inhibitor, not a single other drug in this target family has been approved.
There have been failures, but two new inhibitors are in clinical testing. Both are in Phase I for TB
and both are analogues of Bedaquiline, belonging to the Diarylquinoline chemical classdescribed above.

5.

Macromolecular damage: Nitro group Reactive Species (1). The Otsuka drug Delamanid has
been approved outside the U.S. but remains in Phase III for U.S. development according to the
Otsuka website. Delamanid (OPC-67683) has a very similar structure and works similarly to
Pretomanid as described above.

CDC. (2021). Retrieved from: https://www.cdc.gov/hai/organisms/acinetobacter.html
		Howard, A., et al. (2012). Acinetobacter baumannii. Virulence, 3(3), 243–250.
CDC AR Threats Report, (2019), accessed October 2021.
63
Zervosen, A., et al. (2012). Development of New Drugs for an Old Target — The Penicillin Binding Proteins. Molecules, 17, p.12478—505.
60
61

62

BIO Industry Analysis

19

6.

Macromolecular damage: Riminophenazine reactive species (1). There is an analog ofclofazimine in Phase II for TB. As described above, this drug likely works as a redox cycling
agent that destabilizes membranes and DNA.64

7.

Translation: 30S Ribosome (1). Bipyrocycline, a broad-spectrum antibiotic sharing structuralelements of tetracycline, is in Phase I developed for Community Acquired Pneumonia (CAP). A
clinical development program has demonstrated antibacterial activity on gram-positive andgram-negative bacteria, including Acinetobacter baumannii (G-).

8.

Translation: 50S Ribosome (5 NCEs). There are five 50S ribosome inhibitors in the clinic. Threeof the compounds are oxazolidinone compounds, two are in development to treat
tuberculosis, and one for treating treat gram positive skin infections. The fourth compound is a
ketolide antimicrobial which is a semi-synthetic derivative of erythromycin A. The fifthcompound is aminoglycoside antimicrobial produced from Streptomyces tenebrarius that waspreviously approved for veterinary use.

9.

RNA polymerase (2 NCEs). Both of these NCEs are from TenNor Therapeutics and are hybridsof rifamycin (the primary class of RNA polymerase inhibitors) and another class of antibiotics,
either nitroimidazole class that has macromolecular damaging effects, or the fluoroquinolone
with DNA gyrase/topoisomerase activity. Both are indicated for skin infections.

10. DNA Synthesis: Topoisomerase (4). There are four topoisomerase inhibitors in the clinic, with
two in Phase III. Both Phase III candidates are indicated for urinary tract infections. The othertwo candidates are in Phase II. One is a fluoroquinolone antibiotic indicated for urinary tract
infections. The other Phase II candidate is a narrow spectrum antibacterial with structuralelements of oxazolidinones and quinolones, indicated for the treatment of C. difficile.
The pipeline for indirect-acting antibacterial drug candidates contain nine beta-lactamase inhibitors andfour exotoxin inhibitors. All four exotoxin targets are novel (no prior FDA approval): Staphylococcus aureus
alpha toxin (one mAb in Phase I and one mAb in Phase III), staphyloxanthin (Phase II mAb), Shiga toxins
1/2 (Phase II mAb), and unbound Endotoxin (Phase I mAb). Another indirect-acting pipeline drug works
by potentiating the activity of Tuberculosis drugs (ethionamide and prothionamide) facing resistanceallowing those drugs to overcome resistance.

64

Bvumbi, M. (2020). Activity of Riminophenazines against Mycobacterium tuberculosis: A Review of Studies that Might be Contenders
for Use as Antituberculosis Agents. Chemmedchem, 15(23), 2207-2219.

20

BIO Industry Analysis

Clinical Pipeline by Indication Area
Figure 7 shows the 64 clinical pipeline therapeutics by their indication specific drug programs, of which
there are 72 currently in development. Nearly half of the products are targeted toward the specific strains
M. tuberculosis, C. difficile, Staphylococcus, or Pseudomonas, while others are geared toward eight typesof infection (e.g., skin, joint, abdominal, blood, urinary, CAP, HAP, or general infection). As a percentageof the total pipeline, 38% of programs target C. difficile and M. tuberculosis, and 32% are for urinary tract
infections (UTI) and skin infections.
Some of the antibacterials with organ specific or general indication categories found in Figure 7 havebeen shown to have specific activity against resistant strains and priority pathogens. For example, sixof the eight skin infection programs have activity against S. aureus (MRSA). However, each candidate
under these broad indication pathways has its own unique spectrum of resistant strain efficacy making
categorization difficult. For drug developers, narrow indication claims for clinical trials has potentiallylimiting implications as will be discussed below. Those programs that are designed for specific organisms
tend to be aligned with novelty of target as shown by the orange bars in Figure 7.

Clinical Pipeline by Indica�on

CLINICAL-STAGE DRUG PIPELINE FOR DIRECT-ACTING ANTIBACTERIALS BY INDICATIONAll 72 Drug Programs
0

5

10

15

C. diﬀ

Staphylococcus
A. baumannii

1
1

Pneumonia (CAP)

Abdominal
Blood

2
1

0

Approved Target

38% of pipeline programs are for TB and C diﬀ

12

14

16

18

20

6
3
3
2

Pneumonia (HAP)

0

Abdominal

0

Blood

Novel Target

10

6

Joint

3
1

Pseudomonas

General An�bacterial

5

Joint

0

Pneumonia (CAP)

4

8

2

A. baumannii

Skin

9

6

0

Urinary

13

General An�bacterial

45Staphylococcus

Skin

Pneumonia (HAP)

M. tuberculosis

4

Pseudomonas

2

C. diﬀ

12

Urinaryn Speciﬁcc�on Type

0

20

16

M. tuberculosis

es speciﬁc

28 QIDP Drug Programs

Approved Target
1

Novel Target

Only 5 Novel target NCEs have QIDP
1. Biologics not eligible
2. Some ABX in ex-US trials

Figure 7. Clinical pipeline programs for direct-acting antibacterials by indication (as of October 2021, 72 programs for 64
NCEs). NCE program indications that are species specific are listed at the top and organ specific programs below. Lung
infections are captured by Pneumonia separated into HAP and CAP. It should be noted that QIDP programs for indirectacting and reformulated products are not included in this chart. For example, there is an indirect-acting drug for HAPwith the QIDP designation and one for a reformulated drug indicated for A. baumannii.

BIO Industry Analysis

21

There are 28 antibacterial programs in development that have the FDA Qualified Infectious Disease
Program (QIDP) designation.65 Of these 28 QIDP designated products, only five are for novel targets. The
novel target therapeutics with QIDP designation are only designed to treat C. difficile and S. aureus
specific indications. It is important to note that QIDP designations are currently limited to small molecules.
As presented in Figure 7, 33 of 72 programs are indicated for specific strains. All four strains are listed
as priority pathogens in the most recent lists from the U.S. CDC (2019) and the WHO (2017), presented
in Appendix A1.66 Combined, the lists include 11 other resistant bacterial strains and one family ofbacteria.67 Drug development for bacterial infections has a precedent for being organ specific (e.g.,skin, ear, etc.) and not species specific. This precedent makes it hard to uncover the exact species
targeted within the organ-specific indication. For example, a Phase I drug for “skin infection” mightwork on Staphylococcus (G+), and Klebsiella (G-), or only one and not the other. CAP and HAP include
strains that can lead to pneumonia, but the specific strains targeted are often not listed in the trial
protocol. In many cases, the answer is not known outside of lab testing. As trial enrollment would
require genetic analysis of each strain, this makes data on some resistant organisms hard to obtaineven at the clinical phase. Potential activity against threat pathogens can be estimated based on
preclinical research, but clinical validation of efficacy can be difficult to obtain for every bacterial
strain. The PEW and WHO pipeline analysis, referenced in Appendix A4, provides an assessment ofpipeline products that could potentially target threat pathogens.

Preclinical Pipeline for Antibiotics
According to a 2020 review of the preclinical-stage pipeline for threat pathogens, 407 antibacterial
projects are ongoing.68 A third of these are novel in terms of new class, new target, or new mechanismof action, and many of them are pathogen-specific approaches. Similar to what is reported above forthe clinical pipeline, small companies represent 81% of the preclinical pipeline. Large companies represent
3% of preclinical R&D with academic and non-profit institutions making 15% of the difference.

65

66

67

68

The QIDP designation comes from the Generating Antibiotic Incentives Now (GAIN) Act, Title VIII within the Food and Drug
Administration Safety and Innovation Act (FDASIA). According to an FDA guidance document, this designation offers incentives forthe development of antibacterial and antifungal drugs for human use to treat serious or life-threatening infections. The primary
incentive is a 5-year exclusivity extension for certain applications of drug products that have been designated as a QIDP andapproved under section 505 of the FD&C Act. This 5-year exclusivity extension is added to any exclusivity for which the application
qualifies upon approval - https://www.fda.gov/files/drugs/published/Qualified-Infectious-Disease-Product-DesignationQuestions-and-Answers.pdf
CDC AR Threats Report. (2019). accessed October 2021. Retrieved from: https://www.cdc.gov/drugresistance/biggest-threats.html
and WHO 2020 Antibacterial agents in Clinical Development
The family of bacteria is Enterobacteriaceae and it is listed twice (for CRE and ESBL) in Appendix A1. The family Enterobacteriaceae
includes individual members like Salmonella, Escherichia coli, Klebsiella, and Shigella, even though they are listed separately, withdifferent threat levels, on those lists.
Theuretzbacher, U., Outterson, K., Engel, A., Karlen, A. (2020). The Global Preclinical Antibacterial Pipeline. Nature Reviews
Microbiology, 18, 275-285

22

BIO Industry Analysis

Success Rates
The overall success rate for antibacterial NCEs was found to be higher than that for the industry overall.
Our previously published results showed success rates of 7.9% across all disease areas to bring a drug
from IND to FDA approval (2011-2020, n=12,728 transitions).69 Using the same dataset, and selecting only
antibacterial NCEs, we calculate the success rate to be 16.3% (n=182 transitions). The primary differentiator
is Phase II, with a 48.0% (n=75) success rate for antibacterial NCEs, well above the 28.9% (n=4,933) successrate for the entire industry at Phase II.
The broad infectious disease area had a success rate overall of 13.2% (n=1,170), implying that antibacterial
NCEs have higher success rates than the non-antibacterial group, which includes antiviral, antifungal,
antiparasitic and vaccines.
Refining the dataset further to include only NCEs with novel targets, the Phase I to approval successrate drops to 13% (n=47). However, the low number of transitions could make this unreliable in predicting
future outcomes. In particular, the Phase III data shows only one success and one failure and only one
NCE for a new target (ATP synthase) over the ten-year period analyzed. NCEs for old targets were more
successful as a group and were found to have a higher success rate from Phase I to approval, 19.2% (n=135).
CLINICAL DEVELOPMENT SUCCESS RATES FOR DIRECT-ACTING ANTIBACTERIAL DRUGS 2011-2020
2011-2020

Phase I to II

Phase II to III

Phase III to
NDA/BLA

NDA/BLA to
Approval

Phase I to
Approval

All Diseases

52.0%

28.9%

57.8%

90.6%

7.9%

N

4,414

4,933

1,928

1,453

12,728All Infectious Dis.

57.8%

38.4%

64.0%

92.9%

13.2%

N

403

414

197

156

1,170

ABX NCEs

73.1%

48.0%

56.3%

82.6%

16.3%

N

52

75

32

23

182

Breakdown of
ABX NCEs:

Phase I to II

Phase II to III

Phase III to
NDA/BLA

NDA/BLA to
Approval

Phase I to
Approval

w/Novel Target

78.3%

33.3%

50.0%

100.0%

13.0%

N

23

21

2

1

47

w/Old Target

69.0%

53.7%

56.7%

81.8%

17.2%

N

29

54

30

22

135

Figure 8. Clinical success rates for infectious disease indications and direct-acting antibiotics compared to success rates
for all disease areas combined, January 2011 through January 2020. Data is based on drug program transitions listed in
the Informa Biomedtracker and Pharmapremia databases. (The full dataset for the industry is available at www.
bio.org/iareports)

69

Thomas, D., et al. (2021) BIO Industry Analysis, Informa Pharma Intelligence, QLS Life Sciences. Clinical Development Success Rates
and Contributing Factors 2011–2020. (Available at www.bio.org/iareports)

BIO Industry Analysis

23

There was also difference by modality. Biologic NCEs, with only 45 total transitions, had a lower Phase
I to approval success rate of 12.8% vs. the small molecule NCE success rate of 18.6% (n=161 transitions).
This differs from our finding in the broader industry where biologics, in particular mAbs, tend to havehigher success rates.
We also investigated QIDP designated drug success rates for Phase III. NCE programs with QIDP had
69.6% (n=23) vs. 37.5% (n=16) without QIDP. Phase I and II success rate analysis has the disadvantage of
selection bias as the designation can be given at various phases. This creates a cherry-picking effectresulting in very high success rates.
Suspended programs for novel targets do not overlap significantly with the current pipeline candidate
targets. Only one Phase III novel drug program was suspended during the period analyzed.70 For Phase
II programs, 14 of 21 failed to reach Phase III and seven progressed to Phase III. Among the suspended
targets were UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC), polypeptide
deformylase, Leucyl-tRNA synthetase, mAbs for Staphylococcus and Pseudomonas targets, and a few
microbiome programs. A similar mix of targets was seen in Phase I, albeit for only six suspended novel
drug programs (LpxC, Staphylococcus mAbs, and a few microbiome therapies). No biologics transitioned
from Phase III to BLA.

70

Patel, M., Kaufman, D. (2015). Anti-lipoteichoic acid monoclonal antibody (pagibaximab) studies for the prevention of staphylococcal
bloodstream infections in preterm infants. Expert Opin Biol Ther, 15(4), 595-600. (This antibody program was suspended during the
10-year period of analysis)24

BIO Industry Analysis

Investment into Emerging Antibacterial Companies
Venture CapitalOver the past 10 years (2011-2020) 22 antibacterial companies started their R&D journey by raising theirfirst major financing round, called a series A-1 round. However, these financing rounds only account for
only 2% of the funding provided to start-up biopharmaceutical companies created over this period. This
low percentage shows a stark contrast in the investment of antibacterial companies versus other diseases.
The disparity can also be seen in the amount invested in all antibacterial companies vs. other diseases.
As shown in Figure 9, antibacterial companies received 17-fold less money than oncology companies
for the decade. The biggest disparity was seen in 2020 when oncology companies raised 44x moremoney than antibacterial companies. The acceleration seen in oncology venture investment, and otherareas of medicine such as rare disease, was missed by the antibacterial entrepreneurs in the U.S. Venture
funding for antibacterial companies increased by 29% for the two five-year windows, 2011-2015 vs. 20162020, but 275% for oncology companies and the 175% for all companies in the industry.
2011-2020 VENTURE INVESTMENT INTO U.S. COMPANIESWITH LEAD NOVEL DRUG PROGRAMS IN ONCOLOGY VS. ANTIBACTERIALS

Oncology
Antibacterial

$7

$6.9

$6
$5

$4.7

$4.9

$4
$2.9

$3

2015

$0.2

$0.2

$0.1

$0.2

$0.2

2020

$0.1

2019

$0.2

2018

$0.1

$1.6

2017

$0.1

2014

$0.7

$0.2

2013

$0

$0.8

$1.2

2012

$1

$1.0

2016

$1.9

$2

2011

Venture Investment ($B)$8

Figure 9. Venture funding of companies with lead products in antibacterials vs. oncology, 2011-2020. Venture
investment into oncology is 17x more than the funding received for novel antibacterials companies during
this time period.

BIO Industry Analysis

25

IPOs
Similar to the trends shown in venture capital, investment into newly public U.S. based antibiotics
companies has been sparse to non-existent in recent years. Over the last 10 years there were 12 antibacterial
company IPOs raising $769 million versus 109 oncology companies raising $12 billion (2011-2020). An
alarming trend is the decrease in antibacterial companies going public in the last five years (only 3). In
contrast, during this same time period most other diseases like oncology have shown a large increasein companies going public (71 companies) versus the previous five years (38 companies). Of the 12
antibiotics companies that have gone public in the past 10 years, only five are still active today. Four ofthe companies were acquired (most at fire-sale valuation due to clinical or market failure), two went
through the reverse merger process due to trial failures, and one company that reached FDA approval
simply went extinct post-bankruptcy.
2011-2020 IPO INVESTMENT INTO U.S. COMPANIESWITH LEAD NOVEL DRUG PROGRAMS IN ONCOLOGY VS. ANTIBACTERIALS$6
Oncology$5.1

Antibacterial

$4
$3
$2

$1.5

$0.0

$0.0

$0.0

2020

$0.1

2019

$0.1 $0.2 $0.0

2018

$0.3

2017

$0.1

2016

$0.1

$0.8

2015

$0.2

$1.2

$0.9

2014

2011

$0.0

2013

$0.2

$0

$1.0

$0.9

$1

2012

Amount Raised in IPOs ($B)$5

Figure 10. IPO funding of U.S. companies with lead products in antibacterials vs. oncology, 2011-2020.

26

BIO Industry Analysis

Clinical Trial Initiations for Novel Antibiotics
To assess investment at the clinical level across the industry, we quantified the number of clinical programs
started each year for the last decade. From a starting list of 602 antibacterial trial starts in the TrialTrove
database over the 10-year period 2011-2020, we found 92 that met our criteria for true antibacterial NCE
trial starts (removing nonintervention trials, reformulations, combinations of older drugs and otherduplicate trials per Phase). Further analysis by novelty of target shows that there were 43 trial starts for
NCEs with novel targets.
As shown in Figure 11, clinical trial starts for antibacterial NCEs has declined over the last 10 years, witha peak of 14 in 2016. Comparing the five-year periods 2011-2015 and 2016-2020 shows a decline of 33%(from 55 to 27). For Phase I initiations, the drop was steeper at 46%.
For drug candidates with novel targets, there was a 28% drop (from 25 to 18) when comparing the fiveyear periods. Small company sponsored programs led the decline, dropping 45% from 22 (2011-2015) to12 (2016-2020). For Phase I starts by small companies, the decline was 60%.
2011-2020 CLINICAL TRIAL STARTS FOR
ANTIBACTERIAL DRUG INTERVENTION TRIALS

Antibiotic NCE Trial Starts

16
14

6

4
7

6
4
2

8

6

7
3

5

5

4

7

5

1
3

NCEs w/novel targets

2017

2016

2015

2014

2013

2012

2011

0

5

5

1
2

1

2020

8

7

2019

10

2018

# Trial Starts

12

NCEs w/non-novel targets

Figure 11. Clinical trial starts for antibacterial NCEs, 2011-2020. TrialTrove data accessed October 2021. Trials wereindividually assessed for NCE intervention trials only and trial Phase cohorts de-duplicated. A total of 92 NCE
intervention trials for were initiated during this time period, with 43 for NCEs with novel targets.

BIO Industry Analysis

27

Discussion
Despite the availability of 106 unique direct-acting antibacterial therapeutic entities on the market in the
U.S. and 28 unique antibacterials outside the U.S., there remains a need for alternatives to currently
available drugs that will circumvent bacterial resistance to current medicines. More than 82% of all
antibiotic approvals occurred prior to the year 2000. The majority of the drugs remaining on the market
are facing eventual loss in efficacy due to resistance developed by bacterial strains encountering thesetreatments in the population. For the next generation of antibacterials to fill this gap, there needs to bea well-funded and appropriately rewarded biotech ecosystem for translational science to reach theclinic and beyond.
The majority of antibacterial innovation stems from small, emerging biotechnology companies, as
indicated by 80% of the current clinical pipeline candidates originating in these companies. However,funding has been sparse for these antibacterial developers, and the ecosystem is fragile and failing. Overthe last decade, antibacterial start-ups raised a total of only $2.3 billion in both venture capital and IPOs,
well below other areas in medicine and not enough to compensate for the need of a broad ecosystemand diverse pipeline of candidates. By comparison, over this same decade oncology companies raised$38 billion in venture capital and IPOs, more than 16-fold over the amount invested in antibacterials. To
further place the $2.3 billion for antibacterials into context, consider the following reference points from
non-antibacterial companies: one single cell and gene therapy company was recently able to raise $1.3
billion in just under three years; and other individual small biotechs have recently raised $1 billion in asingle year from follow on offerings.71
Our analysis of clinical trial initiations, a broader proxy for R&D investment trends for both large and small
antibacterial-focused companies, reinforces the picture of an exodus from antibacterials. Phase I trial
initiations declined 46% when compared to the previous five-year periods (2011-2015 vs. 2016-2020).
Phase II and III trial initiations declined 33%. The same percentage drop was seen when segmenting bycompany size, suggesting the wane in large company interest is shared by small companies and theirinvestors. This is particularly concerning as large companies have traditionally been a critical part of theantibiotic ecosystem, with their extensive manufacturing infrastructure and global distribution capacity.
There are only 44 drug programs in the current antibacterial pipeline, excluding the innovative products
for TB and C. difficile. That is far below what is needed to address the 13 threat pathogens outside of TB
and C. difficile listed by CDC and WHO (Appendix A1), based on historic success rates.72 Consider thatfor COVID-19 alone, there were 1,030 drug and vaccines programs launched in 2020-2021, and more than
450 reached the clinic.73 The magnitude of R&D for individual oncology indications also underscores thesize of the funnel that is needed to generate just a handful of meaningful therapeutic options for patients.
For breast cancer alone, there are 160 NCE drug programs in the clinic.74 Unfortunately, the commitment
to antibacterial R&D is narrow by comparison. In fact, for systemic small molecules (the traditional bar
for effective, widely available antibiotics) there is only one Phase III drug in the clinic. Historic successrates for drug development have shown that the number of shots on goal must increase if we are to
see life-saving therapies become available for patients. Furthermore, multiple products on the market
are also needed to ensure real-world success.

		Sana Biotechnology, sold 23.5 million shares at $25 per share ($588 million) in February 2021 and raised more than $700 million in
venture capital since its founding in 2018. During the last decade (2011 to 2020), U.S. antibacterial companies raised just $769 million in
IPOs. Bluebird bio raised more than $1 billion in follow-on offerings in 2017.
72
As a simple example calculation: Assuming at least two new drugs to rely on for each of the 13 pathogens and assuming a similar
distribution of asset progression as found in the current pipeline (35% NCEs in Phase I, 45% in Phase II, and 20% in Phase III), theprobabilities suggest a minimum of 153 candidates would be needed in the pipeline.
73
BIO Covid pipeline tracker: https://www.bio.org/policy/human-health/vaccines-biodefense/coronavirus/pipeline-tracker
74
Based on a search of the Biomedtracker database November 2021
71

28

BIO Industry Analysis

Contrary to what might be expected for a heavily underinvested disease area, the success rate for new
antibacterials was found to be above the industry average. New antibacterials were found to have a
16.3% success rate from Phase I to FDA approval, above the overall industry average of 7.9% for 2011-2020.
New antibacterial therapies with novel targets had a success rate of 13.0%, above average and in linewith the greater infectious disease area. Interestingly, oncology has an extremely low success rate near
5%, yet continues to receive record amounts of investment. This reinforces that there are other factors
preventing investment into antibacterials, as higher rates of success have had little impact.
There are three main factors that have scared off investors from antibacterial development. First, large
companies have been exiting from the space for some time, with very few listed as co-sponsors of small
company pipeline candidates. Without a vested interest from large biopharmaceutical companies,
licensing deals and M&A dry up, souring the incentive for early-stage investors such as venture capitalists.
Second, the majority of recent examples of “successful” biotechs (those that have raised venture capital,
obtained funding through public offerings, obtained FDA support via QIDP, and achieved FDA marketing
approval) have been commercial failures. Investors point to these recent stories of antibacterial company
bankruptcies and acquisitions at fire sale valuations as evidence to avoid investment in this segment of
medicine.75,76 The third factor is the lack of effective policy and regulatory solutions to address the uniquecharacteristics of the antimicrobial marketplace.
The primary issue forcing big pharma out of the antibacterial sector and leaving small company innovators
empty handed is that the traditional market dynamics do not exist for antimicrobials, and this has notbeen resolved through new policies. First, new antimicrobials will primarily be used as “last line” therapies
for use in hospitals when other options are ineffective. These products are short duration therapies andwill experience slow uptake since they are usually used sparingly to preserve effectiveness. Novelantimicrobials are also generally undervalued by reimbursement systems relative to the benefits theybring society. Finally, hospital bundled-payment reimbursement mechanisms can discourage use ofnovel antibacterials, even when they are the most appropriate treatment for a patient, contributing not
only to market challenges but also patient access to novel products. Taken together, these challenges
create a market with little to no return on investment for antibacterial medicines.
This market reality for antibiotics, due to appropriate stewardship implementation, cheap available
generics, oscillations in waves of infectivity (potentially non-existent in pre-crisis periods), means thatboth drug market volumes and drug pricing are under unique pressures that turn investment return
models negative.77
Solutions: From government and non-profit funding and regulatory incentives to market fixes
Ongoing conversations about policy solutions span the entire pathway of drug development and access:early-stage investment (push mechanisms for research), late-stage investment (push mechanisms fordevelopment), clear and efficient regulatory pathways (regulatory incentives for development), and,
importantly, the post-approval market incentives (pull mechanisms). There is broad alignment acrossacademia, industry, policymakers, and other stakeholders that all four modes of incentivizing innovation
are needed to stabilize and sustain the antimicrobial ecosystem and address the ongoing fight against
AMR. As illustrated in Appendix A2, these solutions, and the entities that drive them, are interconnected
and dependent on each other.

Plackett, B. (2020). No money for new drugs: Despite an overwhelming global need for pharmaceutical companies to develop more
antibiotics, there’s little financial incentive to encourage them to act. Nature, 586, S50.
76
		Recent examples include Achaogen, a company with an approved antibiotic to treat resistant Infections, that filed for bankruptcy inspring 2019, less than a year after FDA approval. A second company with four antibiotics on the market, Melinta Therapeutics, filed forbankruptcy protection in late 2019 and restructured.
77
		Klug, D., et al. (2021). There is no market for new antibiotics: this allows an open approach to research and development. Wellcome
Open Res., 6, 146.
75

BIO Industry Analysis

29

Early-stage investment (push mechanisms for research). The early funding of new target discovery
at the lab bench must be consistent and sizable. This starts with government funding and grants (e.g.,
NIAID, BARDA, CARB-X etc.), and philanthropic foundations and institutes. However, the early-stage
funding that needs to quickly follow these efforts must support new drug candidate discovery byfunding chemists and biochemists to make the drug entities themselves. This is the phase where angel
investors, entrepreneurs, and venture capitalists have traditionally converged to enable successful drug
discovery. Small companies account for roughly 70% of drug candidates across the industry, and theirfunding is heavily reliant on this investment capital.78 However, as noted above for antibacterials, these
traditional sources of funding are not supplying the investment needed. To solve this deficiency in theecosystem, in recent years other creative hybrid models for funding have been launched, leading topromising NCEs. For example, a global non-profit partnership, CARB-X, recently completed five yearsof funding to support early development of innovative products, totaling over $360 million across 92
projects in 12 countries.79 However, as candidates emerge from this discovery stage, they will go nowhere
unless the following three solutions are in place.
Regulatory incentives for development. In the last decade, multiple regulatory measures have beentaken to change the efficiency and incentives for drug developers. For example, the Generating Antibiotic
Incentives Now (GAIN) Act of 2012 brought forward the Qualified Infectious Disease Product (QIDP)
designation to pipeline candidates. The QIDP designation provides eligibility for priority FDA review,
fast-track designation, and an additional five years of market exclusivity.80 There have been 17 NCE
approvals with QIDP.81 In 2016, the Limited Population Pathway for Antibacterial and Antifungal Drugs(LPAD) was introduced in the U.S. as part of the 21st Century Cures Act. Amikacin and Pretonamid were
the first two drugs approved under this pathway in 2018 and 2019, respectively.82 In 2017, the U.S. Center
for Drug Evaluation and Research (CDER) issued updated FDA guidance on clinical trial design for
antibacterials. All of these regulatory steps acknowledge the hurdles industry is facing in the antimicrobial
arena and take steps to streamline development. However, for drug developers, technical issues withtrial enrollment and running large, complex comparative effectiveness studies remain as late-stage obstacles.83
Late-stage investment (push mechanisms for development). Small companies that may emerge witha candidate from early-stage research often struggle to obtain funding for the complex and costly Phase
II and III trails. Multi-entity funds, such as the recent AMR Action Fund, can serve to fill this gap.84 Other
public private partnerships, such as BARDA’s Project BioShield program or BARDA’s Broad Spectrum
Antimicrobials program can also provide support to accelerate later stage research and development.
The TB Alliance is a successful example of non-profit funding of clinical-stage development, with sevenproducts currently in trials.

BIO’s interactive clinical pipeline review available at https://www.bio.org/fda-approvals-clinical-development-pipeline
CARB-X investments. Retrieved from: https://carb-x.org/carb-x-news/carb-x-celebrates-five-years-of-progress-in-early-stage-product-development-against-antibiotic-resistant-bacteria/. Others examples can be found in Appendix A2 and A3.
80
Schneider, M., Harrison, N. R., Daniel, G. W. & McClellan, M. B. (2020) Delinking US Antibiotic Payments through a Subscription Modelin Medicare. Retrieved from: https://healthpolicy.duke.edu/publications/delinking-us-antibiotic-payments-throughsubscription-model-medicare
81		See the BIO FDA tracker’s regulatory filter: https://www.bio.org/fda-approvals-clinical-development-pipeline.
82
FDA website, retrieved Nov 2021: https://www.fda.gov/drugs/development-resources/limited-population-pathway-antibacterialand-antifungal-drugs-lpad-pathway
83
Bart, S., et al. (2021). Geographic Shifts in Antibacterial Drug Clinical Trial Enrollment: Implications for Generalizability. Clinical
Infectious Diseases, 72, (8) p. 1422–1428
84
AMR Action Fund details accessed December 2021 at https://www.amractionfund.com/
78
79

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Market-based mechanisms – Pull incentives and Reimbursement Reform. Policy reforms that are notin place at the moment – and are most critically needed – are solutions to address the most disabling
pillar of the ecosystem: the marketplace. The investment issues and anemic pipeline presented in thisreport are a result of broken market dynamics that create a risk-benefit imbalance when it comes todeveloping and launching antibiotics. With average sales revenue for antibiotics well below the thresholdfor remaining commercially viable (due to both price and volume), and with similar drug development
costs to other disease areas, the incentive to invest for comparable ROI – and in some cases any ROI – ismissing. Unlike other areas of drug development with potential benefits commensurate with risk taken
and value delivered to patients, the private sector pathway for antibacterials does not work. Unlike the
obstacles seen with chronic diseases, such as the inability to stratify patient populations, lack ofunderstanding of the pathophysiology, and the challenging and costly regulatory requirements anddifficult reimbursement environment, the antibiotic developers are facing a more nuanced market issue– the market for these types of novel antibiotic products does not exist in the traditional pharmaceutical form.
To address the unique market challenges for antibacterials, a combination of two complementary postapproval incentives is necessary: a pull incentive to ensure sustainable investment into the AMR productpipeline, and reimbursement reform to stabilize the commercial marketplace and improve patient access.
First, new economic incentives that reward successful innovation at a level sufficient to attract further
R&D may serve to pull participants back into the fray. Studies estimate that incentives in the range of$1-4 billion per successful launch of a new and innovative antibiotic are needed globally. Several typesof “pull incentives” have been proposed and pilots are ongoing to address the broken marketplace for
antibacterials.85 One solution is an incentive, such as a market entry reward or subscription model, which
rewards the successful approval of a novel AMR medicine that meets critical unmet medical needs. Thismechanism could provide an important incentive for private investment in these products by providing
a return on investment for AMR programs that is competitive with other areas of potential R&D investment.
This could also be achieved through a subscription model that would allow reimbursement to be partiallyde-coupled from volume of sales to reduce the incentive to inappropriately use novel antibiotic medicines.
The bipartisan Pioneering Antimicrobial Subscriptions to End Upsurging Resistance (PASTEUR) Act,
introduced in both chambers of Congress in 2020 (and reintroduced in 2021), is one policy proposal
currently under consideration which would establish such an incentive.
Reimbursement reform, if combined with appropriate valuations, could play a complementary role tostabilize the antibiotics market. Current Medicare in-hospital bundled-payment mechanisms may
discourage the use of novel antimicrobial medicines – even in situations where they are more clinicallyappropriate – as hospitals will lose money using these novel products on these patients. This creates abarrier to patient access and contributes to the poor uptake of AMR medicines from companies struggling
to remain commercially viable. One solution to this problem would be for qualifying antimicrobials toreceive separate payment under in-hospital Medicare reimbursement. This would ensure hospitals areadequately reimbursed for novel antimicrobials, enabling doctors to prescribe the most appropriate
antimicrobial based on clinical, not financial, considerations. This separate payment would ensure patient
access when appropriate and help address the poor market uptake of AMR medicines. This reform could
be achieved either through the Centers for Medicare and Medicaid Services (CMS) current rulemaking
authorities, or a legislative proposal such as the Developing an Innovative Strategy for Antimicrobial
Resistant Microorganisms (DISARM) Act, introduced in Congress in 2020 with bipartisan support. 86
All innovation needs a functional, efficient ecosystem for it to succeed in generating life-saving products.
The Biotechnology Innovation Organization (BIO) and member companies view innovation as the key
to tackling the emerging threat of antibiotic resistance. Policies that stimulate greater investment in
antibiotic R&D through a combination of both push and pull incentives, are necessary to achieve this goal.

85

86

Outterson, K. Estimating. (2021). The Appropriate Size Of Global Pull Incentives For Antibacterial Medicines. HEALTH AFFAIRS, 40,(11) p.1758–1765
Text for the Disarm Act (H.R. 4127) can be accessed at https://www.congress.gov/bill/117th-congress/house-bill/4127

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31Appendix
Appendix A1. CDC and WHO pathogen threat lists
Organism

CDC 2019

WHO 2017

Acinetobacter baumannii (G-) [CRAB]

UrgentCriticalEnterobacteriaceae [family*] (G-) [CRE]UrgentCriticalNeisseria gonorrhoeae (G-) [CR, FR]

UrgentHigh

Clostridioides difficile (C. diff) (G+)

UrgentNot listed

Enterobacteriaceae [family*] (G-) [ESBLE]

Serious

Critical

Pseudomonas aeruginosa (G-) [CRPA]

Serious

CriticalEnterococcus faecium (G+) [VRE]

SeriousHigh

Staphylococcus aureus (G+) [MRSA,VRSA]

SeriousHigh

Campylobacter spp. (G-) [FR]SeriousHigh

Salmonellae Typhi (G-) [FR]SeriousHigh

Streptococcus pneumoniae (G+)

SeriousMedium

Shigella spp. (G-) [FR]SeriousMediumMycobacterium Tuberculosis (TB) (G-/+)

Serious

Not listed

Streptococcus pyogenes (Group A) (G+) [ER]Concerning

Not listed

Streptococcus agalactiae (Group B) (G+) [CR]Concerning

Not listed

Helicobacter pylori (G-) [ClR]

Not listed

High

Haemophilus influenzae (G-) [AR]Not listed

MediumFigure A1. CDC and WHO list of antibiotic resistance bacterial threats. CR = carbapenem-resistant, VR= vancomycinresistant, MR = methicillin-resistant, ClR = clarithromycin-resistant, FR = fluoroquinolone-resistant, AR = ampicillinresistant. M. tuberculosis and C. diffile are covered in recent WHO reports, but not on the original pathogen list of 2017.
*Family Enterobacteriaceae includes Escherichia coli, Klebsiella, Salmonella, and Shigella. The CDC list is available athttps://www.cdc.gov/drugresistance/biggest-threats.html and the WHO list at https://www.who.int/news/item/2702-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed. (Mycobacterium tuberculosis
and Clostridioides difficile are covered in recent WHO reports, but not on this threat list)

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Appendix A2. Entities involved in Antibacterial Innovation

Figure A2. CARB-X diagram of interconnected entities along the R&D process for antibacterial development.
Accessed January 2022 at https://carb-x.org/resources/presentations/

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Appendix A3. Abbreviations for entities involved in antibacterial innovation
Abbr

Name

LaunchYear

Description

Acronyms for Push Collaborations, Initiatives, and Funds
Action FundAMR Action Fund2020

Established by 23 pharmas for AMR trials in Phase II and III ($1B)

CARB-X

Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator

2016

Established by BARDA, Wellcome Trust, Germany’s BMBF, UK's
GAMRIF, BMGF, and Boston Uniiversity (with preclinical services by
NIH NIAID)

REPAIR

Replenishing and Enabling the Pipeline for Anti-Infective
Resistance Impact Fund2018

Established by Novo Holdings for early-stage AMR drug start-ups($165M)

GARDP

Global Antibiotic Research and Development Partnership

2016

Established by WHO and DNDi for new for AMR drug development (€100M, as of 2021)

ENABLE

European Gram-negative Antibacterial Engine

2014

Established by IMI for early-stage discovery and development ofantibiotics against Gram-negative bacteria

JPIAR

Joint Programming Initiative on Antimicrobial Resistance2013

International collaborative of 28 nations and the EC for AMR

Acronyms for Pull Initiatives/Incentives for Antimicrobial Innovation
NHSEI pilot

NHS England and NHS Improvement pilot study for
antibiotic subscription model

2019

NICE-sponsored antibiotic subscription pilot project

PASTEUR ACT

Pioneering Antimicrobial Subscriptions To End Up Surging Resistance Act of 2020

2020

U.S. Senate bill that includes a subscription contract for novel
antibacterials

Acronyms for Non-Profits involved in Antimicrobial Innovation
BMGF

Bill & Melinda Gates Foundation2000

Non-profit, private philanthropic foundation

Pew

Pew Charitable Trusts

1948

Non-profit organization that seeks to improve public policy,
inform the public

DNDi

Drugs for Neglected Diseases initiative2003

Non-profit organization developing new treatments for neglected patientsTBA

TB allliance2000

Non-profit product development partnership (PDP)

Wellcome Trust

1936

Non-profit foundation focused on health research based in
LondonInfectious Diseases Society of America

1963

Medical association for infectious disease specialists

Wellcome
IDSA

Acronyms for InterGovernment Entities involved in Antimicrobial Innovation
WHO

World Health Organization

1948

United Nations coordinatation of health affairs related to antibacterials

IMI

Innovative Medicines Initiative

2012

Public-private partnership in Europe, runs New Drugs for Bad
Bugs (ND4BB) and DRIVE-AB (pull incentive research)

Acronyms for IntraGovernment Entities involved in Antimicrobial Innovation
GAMRIF

Global Antimicrobial Resistance Innovation Fund2016

UK Government’s Department of Health and Social Care program

DZIF

German Centre for Infection Research founded byGermany’s Federal Ministry of Education and Research(BMBF)

2012

Germany's government funding source of antibiotic resistanceand for antibacterials

BARDA

Biomedical Advanced Research and Development
Authority

2006

U.S. Government public/private partnerships for antibacterial
medical countermeasures

NIAID

National Institute of Allergy and Infectious Diseases

1955

U.S. Government funding to conduct and support research on
antibacterials

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Appendix A4. Methodology and Comparison with other Pipeline Reports
This report is restrictive in its definition of “antibiotics,” focusing exclusively on antibacterials (i.e., does
not include antifungal and anti-protozoan drugs), and including those that act by killing or directly inhibiting growth of any bacteria. We include drugs that have been approved ex-U.S. but remain in thepipeline under a U.S. regulatory pathway.
Two other recent reports for this field can be found at the WHO and PEW websites.87,88 Differences
between the WHO 2020 clinical pipeline report with this report are that WHO excludes topical treatments
and does not separate beta-lactamases nor exotoxin mAbs as indirect-acting antibacterials. With thosecriteria, WHO reported 68 clinical therapies vs. the 78 antibacterials reported here (as 64 direct-acting +14 indirect-acting antibacterials). Although 43 direct-acting drugs overlap in the reports, some recent
updates to programs in this report (as of November 2021) led to some suspended drugs and new
Phase I drugs.
The PEW analysis, which is updated annually (2014-2021), has numerous differences in methodology
compared with this report. The PEW 2020 analysis of antibacterials (published in 2021) excludes TB andH. pylori drugs and excludes topical and inhaled products. With those criteria, PEW reported 69 clinicalstage therapies (43 traditional and 26 non-traditional therapies).
One difference from other reports includes the categorization of nitroimidazoles: (e.g., Pretonamid,
approved in 2019, and Delamanid, approved ex- U.S. but in Phase III in the U.S.). They are commonly
assigned to either fatty acid or mycolic acid synthesis pathway (as they block the generation of methoxy/keto mycolic acids), but more evidence suggests a broader targeting of the activated species explaining
its ability to work on rapidly growing and latent mycobacterial cells.89,90,91,92
Antibacterial vaccines were not included. However, with the pipeline thin and slow to expand, could
vaccines be applied solution to resistant bacterial threats? Unfortunately, the current clinical pipeline forbacterial vaccines contains only 11 new vaccines in the clinic for seven bacteria strains. There are also 32
second generation vaccines (for eight bacteria strains with a prior vaccine approval). This is not encouraging
as the success rate for bacterial vaccines is lower than for antibacterials. From Phase I to FDA approval,
bacterial vaccines had a 10% success rate for the period 2011-2020.

PEW report on 2020 pipeline, accessed December 2021: https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development (non-traditional pipeline: https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2017/nontraditional-products-for-bacterial-infections-in-clinical-development)88
WHO report on 2020 pipeline, accessed December 2021: https://www.who.int/publications/i/item/9789240021303
89
Babtista, R., et al. (2018). Untargeted metabolomics reveals a new mode of action of pretomanid (PA-824). Nature Scientific Reports,
8, Article number: 5084.
90
Thakare, R., et al. (2020). Pretomanid for the treatment of pulmonary tuberculosis. Drugs Today, 56(10), 655-668.
91
		Liu, Y., et al. (2018). Delamanid: From discovery to its use for pulmonary multidrug-resistant tuberculosis (MDR-TB). Tuberculosis(Edinb), 111, 20-30.
92
Marrakchi, H., et al. (2014). Mycolic Acids: Structures, Biosynthesis, and Beyond. Chemistry &Biology, 21(1), 67-85.
87

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For more reports from BIO’s Industry Analysis team,please visit wwww.bio.org/iareports

Authors
David Thomas, CFA
Vice President, Industry Research
Biotechnology Innovation Organization (BIO)
dthomas@bio.org

Chad Wessel
Director, Industry Research & Policy Analysis
Biotechnology Innovation Organization (BIO)

Acknowledgements
We would like to acknowledge BIO staff (Cartier Esham, Emily Wheeler, Phyllis Arthur, Khushboo Sharma,
Dan Malessa) and Kevin Outterson, Richard Alm, Joe Larsen, and Greg Frank for their review.

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www.bio.org/iareports

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